Abstract/Project Summary Glomerular disease is the third leading cause of end stage kidney disease in the US, with its related health care costs estimated at $4.1 billion annually. Immunosuppressive (IS) drugs are the primary therapies for most glomerular diseases, but ~20-50% of patients fail to achieve a remission. Unfortunately, in the absence of biomarkers to predict treatment responsiveness, many patients receive prolonged yet ineffective IS therapy, leaving them at high risk for both toxic side effects and disease progression. Since the prognostic factors and specific molecular pathways that are the most critical regulators of the various glomerular diseases are not yet known, there is an urgent need to develop strategies to prevent drug-induced toxicity, and to identify more targeted and effective treatments for glomerular disease. Our long-term goal is to identify prognostic biomarkers and molecular pathways that regulate glomerular injury, and use this knowledge to develop predictive biomarkers and more targeted treatments for glomerular disease. The specific objective of this proposal is to identify diagnostic and predictive biomarkers and novel molecular pathways/targets for each of the four CureGN glomerular diseases by integrating state-of-the-art proteomic and metabolomic analyses of serial plasma samples from pediatric glomerular disease patients. Based on this, we hypothesize that integrated proteomic and metabolomic analyses of serial clinically and histologically phenotyped pediatric plasma samples will identify novel biomarkers that predict treatment responsiveness, as well as molecular targets for targeted glomerular disease treatments. CureGN is a prospective observational study to clinically phenotype and collect serial blood and urine samples from 2,400 children and adults with four of the most common types of glomerular disease: MCNS, FSGS, MN, and IgAN. The rationale for this proposal is that integrating proteomic and metabolomic analyses of serial clinically and histologically phenotyped pediatric plasma samples will enable identification and validation of novel biomarkers that can predict glomerular disease treatment responsiveness, as well as novel molecular targets for future treatments. To test our hypothesis, we propose the following Specific Aims: 1) To compare sequential pediatric plasma proteomic and metabolomic signatures to identify predictive biomarkers, and to differentiate molecular pathways that are distinctive or common among all four CureGN glomerular diseases, 2) To integrate proteomic and metabolomic data to identify combined predictive biomarkers, and to differentiate molecular pathways that are distinctive or common among all four CureGN glomerular diseases, and 3) To validate candidate biomarkers in independent CureGN pediatric samples. These studies will apply a state-of-the-art integrated proteomic and metabolomic systems biology approach to a large cohort of phenotyped pediatric plasma samples to identify and validate novel biomarkers that can predict treatment responsiveness, and identify new molecular targets for potential future glomerular disease treatments.